NDM-1, the acronym of New Delhi metallo-β-lactamase-1, is reported in an article published in a famous English medical magazine—“The Infectious Diseases” on Aug. 11, 2010. The bacteria carrying the gene may produce a special β-lactamase, the active part of the enzyme is metal ion, and it was firstly discovered in the capital of India, New Delhi, so it is named NDM-1. Generally, the NDM-1-producing bacterial are mainly Escherichia coli and Klebsiella pneumonia, which can cause both nosocomial infection and community infection, including urinary tract infection, bloodstream infection, pneumonia, catheter-related infection, wound infection and so on. Approximately 200 antibiotics on the market in the world have little effect on such new “super bacterium” (FANG Mi, et al. 2011). Therefore, there is an immediate need to find drugs capable of effectively inhibiting infections caused drug-resistant bacteria such as “super bacterium” producing NDM-1, etc.
Piperacillin sodium is semisynthetic penicillin antibiotic, clinically applied to septicemia, upper urinary tract and complicated urinary tract infection, respiratory tract infection, biliary tract infection, abdominal infection, pelvic cavity infection and skin and soft tissue infection etc. induced by sensitive Enterobacteriaceae bacteria, pseudomonas aeruginosa and Acinetobacter. Sulbactam sodium (SBT) is a β-lactamase inhibitor, which is effective against penicillinase produced by drug-resistant staphylococcus aureus, pneumobacillus and Escherichia coli, and can penetrate cell walls to inhibit β-lactamase produced in cells by bacteria; moreover, SBT itself can also obviously inhibit cephalosporinase produced by Bacteroides fragilis, and effectively kill the bacteria of Acinetobacter (ZHANG Chunhui, et al, 2004). The combination of piperacillin sodium and sulbactam sodium has good stability, exhibits strong antimicrobial activity against clinically common enzyme-producing bacteria, expands antibacterial spectrum, and has wide application in domestic and foreign markets (SUN Mingjie, et al, 2007).
Crystal form is an important physicochemical property of a drug, and in the aspect of drug quality control, different crystal forms may have different stabilities and thereby affect drug quality. If the crystal form of a drug is fixed, its quality is more stable and is easier to control, otherwise, quality difference may occur between drug batches, such that the stabilities of the drugs differs from each other.
Patent application JP2007099763A discloses two new crystals of piperacillin sodium monohydrate, named type I crystal and type II crystal respectively. The two crystal forms are characterized by having following characteristic diffraction angles (2θ) respectively in PXRD: 3.9°, 4.6°, 5.6°, 6.7°, 9.8° and 7.3°, 7.9°. The patent states that the properties, such as dissolution, moisture absorption, purity, stability, etc. of piperacillin sodium of the two crystal forms are all better than those of amorphous piperacillin sodium.
Wherein, the preparation method of type I crystal comprises: adding certain amount (e.g. 60 g) of piperacillin sodium into certain amount of alcohol aqueous solution (e.g. ethanol 120 ml+water 12 ml), filtering off insoluble substances, sequentially adding certain amount of solvent (e.g. tetrahydrofuran 300 ml), dropping certain amount of acid solution (e.g. acetic acid 6 ml+tetrahydrofuran 60 ml), then stirring at 15-20° C. for 24 h, filtering out the resulted crystal, and washing with alcohol solution (e.g. ethanol+/−other solvent) to obtain the target product with water content of 3.2%.
The preparation method of type II crystal comprises: adding certain amount (e.g. 2 g) of piperacillin sodium into certain amount of alcohol aqueous solution (e.g. ethanol 4 ml+water 1 ml), filtering off insoluble substances, adding certain amount of base (e.g. sodium acetate 0.03 g) and certain amount (12 ml) of ethanol, then stirring at 5° C. for 24 h, filtering out the resulted crystal, and washing with ethanol to obtain the target product with water content of 3.2%.
Patent JP2007246514A discloses two piperacillin sodium crystals, i.e. piperacillin sodium monohydrate and new piperacillin solvate crystal, named type III crystal and type IV crystal respectively. The two crystal forms are characterized by having following characteristic diffraction angles (2θ) respectively in PXRD: 6.1°, 10.2°, 12.4°, 15.6°, 15.8°, 18.6° and 5.3°, 6.1°, 8.7°, 10.2°, 12.4°, 18.6°. The patent shows that compared to amorphous piperacillin sodium, the two crystal forms have good solubility, low moisture absorption and smaller powder volume, easy filtration and drying in industrial production, high purity, and low related substances content.
Wherein, the preparation method of type III crystal comprises: adding certain amount (e.g. 2 g) of piperacillin sodium into certain amount of a mixture solution of ketone, DMF and water (e.g. butanone 2 ml+DMF 3.8 ml+water 0.6 ml), then adding certain amount of ketone again (e.g. butanone 10 ml), filtering off insoluble substances, standing at 5° C. for 24 h, filtering out the resulted crystal, and sequentially washing with certain amount of ketone solution (e.g. butanone 3 ml+DMF 0.9 ml+water 0.1 ml) and certain amount of ketone (e.g. butanone 6 ml) to obtain the target product with water content of 3.2%.
The preparation method of type IV crystal comprises: adding certain amount (e.g. 2 g) of piperacillin sodium into certain amount of mixture solution of dioxane, water and another solvent (e.g. dioxane 6 ml+water 1.2 ml+acetone 13 ml), filtering off insoluble substances, standing at 5° C. for 24 h, filtering out the resulted crystal, and then washing with certain amount of ketone (e.g. acetone 10 ml) to obtain the target product with water content of 3.0% and dioxane content of 7.3%.
Patent application CN200880003783.1 discloses two new piperacillin sodium monohydrate crystal forms, named type V crystal and type VI crystal respectively. The two crystal forms are characterized by having following characteristic diffraction angles (2θ) respectively in PXRD: 3.7°, 5.5°, 7.3°, 11.6°, 14.5°, 18.0° and 5.6°, 7.8°, 12.3°, 15.5°, 17.5°, 23.3°, 24.8°, 28.5°. The patent shows that compared to amorphous piperacillin sodium, the two crystal forms have good solubility, low moisture absorption, easy filtration and drying in industrial production, high purity, and low related substances content.
Wherein, the preparation method of type V crystal comprises: adding certain amount (e.g. 50 g) of type III piperacillin sodium crystal into a pressure vessel (inner diameter of 68 mm, length of 180 mm) equipped with a filter, and under certain temperature (e.g. 40° C.) and certain pressure (e.g. 20 MPa), treating with carbon dioxide mixture at least added with a solvent (e.g. carbon dioxide: methyl acetate=96:4) to obtain the product.
The preparation method of type VI crystal comprises: adding certain amount (e.g. 200 g) of type III piperacillin sodium crystal into a pressure vessel (inner diameter of 68 mm, length of 180 mm) equipped with a filter, and under certain temperature (e.g. 40° C.) and certain pressure (e.g. 40 MPa), treating with pure carbon dioxide for a period of time (e.g. 4 h) to obtain the product.
Furthermore, as to the crystal form of sulbactam sodium, ZHOU Fufu et al. studied the effect of reaction solvents ethyl acetate, acetone, ethanol and methanol on the crystalline state of sulbactam sodium, and discovered by observing with a polarizing microscope that in different solvents, the crystalline states of dry reacted sulbactam sodium products have large difference. When acetone is used as solvent, the crystal of sulbactam sodium is similar to a thin disc body, and has serious dry product agglomeration; when ethyl acetate is used as solvent, the crystal of sulbactam sodium is similar to a cylinder and has large crystal body and good liquidity; when ethanol is used as solvent, the crystal of sulbactam sodium is similar to irregular taper or fan-shaped adhered body and has good liquidity; and when methanol is used as solvent, the crystal of sulbactam sodium is scattered long thin needle-shaped body, and has small bulk density and poor liquidity, wherein the liquidity can be properly improved after ground (Journal of Huaihai Medicine, 2005, 9(23), 423). However, the studies above only provided simple morphology description graph, and there are no systemic comprehensive studies such as powder X-ray diffraction, TG/DSC, etc., i.e. there are no studies performed on the crystal form of sulbactam sodium.
Drug validity period is approved drug service life, representing the time limit capable of ensuring that the drug quality is stable under specified storage conditions. During hospital purchasing process, it is generally required to purchase drugs having a validity period of at least over 1 year; and during storage and pharmacy dispensing processes, the situation that drugs cannot be dispensed for having passed or going to pass the validity period often occurs. The validity periods of respective preparations of current commercial piperacillin sodium and sulbactam sodium are both 24 months. Since antibiotic experiences a long process from production to clinic, including testing, transporting, etc, and clinical dosage of antibiotic is large, problems such as returning and exchanging or difficult selling may easily happen sometimes due to very short drug validity period. If the stabilities of related products of piperacillin sodium and sulbactam sodium can be improved to extend drug validity periods, its economy and safety may certainly be improved. However, although compound preparations of piperacillin sodium and sulbactam sodium have good application value clinically (SUN Mingjie, 2007), there are no studies and reports regarding the crystalline state of the mixture crystal thereof, nor that the product quality is controlled through the crystal form during production processes.
Drug cocrystal is formed by binding active drug ingredients with cocrystal formations in a lattice via non covalent bond such as hydrogen bond, π-π action, Van der Waals' force, etc. It is a new drug in a solid form, and has great application value in pharmaceutics. Compared to simplely mixing of two or several drugs, drug cocrystallization can introduce new components without changing the covalent structure of the drug, and greatly improve the stability of compound drugs. Therefore, the study on drug cocrystal is useful for selecting and improving drug therapeutic effect, ensures the stability of content and purity and crystal form consistency of solid raw drugs and preparations thereof during preparation and storage processes, and can extend drug validity period.
The character of commercial piperacillin sodium is white or off-white amorphous powder, so the compound piperacillin sodium-sulbactam sodium using it as raw material (no adjuvants) are also amorphous solid, which ultimately results in that the validity periods of current commercial compound preparations of piperacillin sodium and sulbactam sodium only reach 24 months barely. Thus, industrially, there still is a desire to discover a compound preparation of piperacillin sodium and sulbactam sodium with more stable form, and by improving the stability of compound drugs, the validity period of the drugs is extended, and its economy and safety is certainly improved.